17-63477099-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000789.4(ACE):c.5G>A(p.Gly2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000611 in 1,309,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

ACE
NM_000789.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.967

Publications

5 publications found

Variant links:

Genes affected

ACE (HGNC:2707): (angiotensin I converting enzyme) This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]

ACE Gene-Disease associations (from GenCC):

renal tubular dysgenesis - ACE
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
renal tubular dysgenesis of genetic origin
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31999275).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	NM_000789.4	MANE Select	c.5G>A	p.Gly2Glu	missense	Exon 1 of 25	NP_000780.1	P12821-1
ACE	NM_001382700.1		c.-231G>A		5_prime_UTR	Exon 1 of 22	NP_001369629.1
ACE	NM_001382701.1		c.-610G>A		5_prime_UTR	Exon 1 of 23	NP_001369630.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	ENST00000290866.10	TSL:1 MANE Select	c.5G>A	p.Gly2Glu	missense	Exon 1 of 25	ENSP00000290866.4	P12821-1
ACE	ENST00000953328.1		c.5G>A	p.Gly2Glu	missense	Exon 1 of 25	ENSP00000623387.1
ACE	ENST00000884279.1		c.5G>A	p.Gly2Glu	missense	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

1886

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000259

AC:

AN:

1158324

Hom.:

Cov.:

AF XY:

0.00000178

AC XY:

AN XY:

562234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22734

American (AMR)

AF:

0.000356

AC:

AN:

8426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14802

East Asian (EAS)

AF:

0.00

AC:

AN:

25900

South Asian (SAS)

AF:

0.00

AC:

AN:

40950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

968562

Other (OTH)

AF:

0.00

AC:

AN:

47004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151414

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41336

American (AMR)

AF:

0.000329

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5078

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67768

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.46

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.32

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

0.97

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.15

REVEL

Benign

0.037

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0090

Vest4

0.42

MutPred

0.19

Gain of solvent accessibility (P = 0.0789)

MVP

0.69

MPC

0.12

ClinPred

0.49

GERP RS

3.4

PromoterAI

0.41

Neutral

(source)

Varity_R

0.14

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over